Synthesis of the naturally occurring prenylated coumarins balsamiferone and cedrelopsin by domino reactions

Regioselective one step synthesis of naturally occurring prenyl coumarin balsamiferone is described using domino Wittig reaction, 3,3-sigmatropic rearrangements and deprenylation, while regioselective synthesis of cedrelopsin is described via domino Wittig reaction, prenylation and deprenylation..


Introduction
Coumarin is a oxygen heterocycle widely distributed throughout the plant kingdom. 1 Coumarins have received considerable attention, since they exhibit diverse biological activities such as anti HIV, antimalarial, antibacterial, anticancer, cytotoxic, antitumor, antihypertension, antiarrhythmia, anti osteoporosis, pain relief, preventing asthma and antisepsis. 2 Several of these compounds have isoprenoid units (mostly prenyl/isoprenyl) attached at different positions in the benzopyran ring system. 3For example gravelliferone 1 [3-(1,1-dimethylallyl)-6-(3,3dimethylallyl)-7-hydroxycoumarin] isolated 4 from Ruta graveolens, balsamiferone 2 [3,6-di-(3,3-dimethylallyl)-7-hydroxycoumarin] isolated 5 from Amyris balsamifera, and 6,8diprenylumbelliferone 3 isolated 6 from Citrus species are three typical diprenylated coumarins, while cedrelopsin 4 isolated from the bark of Cedrelopsis grevei 7 has one prenyl group (Figure 1).Domino reactions 8 play crucial role in the biosynthesis of natural products.Chemists are interested in emulating these reactions in laboratory due to the tremendous savings they offer in terms of time, energy and cost as compared to conventional sequential synthesis.It also provides opportunity to construct complex target compounds by the introduction of several diversity elements in a single chemical event.It can also be exploited to make libraries of structurally diverse compounds.Typically, purification of products resulting from domino reactions is also simple since all the organic reagents employed are consumed and are incorporated into the target compounds.Several methods/reviews are reported for the construction of complex molecular framework using domino reactions.

Results and Discussion
In our earlier communication 10 we had used domino Wittig reaction, double Claisen-Cope rearrangements for the one pot synthesis of gravelliferone 1.This is one of the shortest syntheses of this natural coumarin.During this experiment, we also obtained 6,8-diprenylumbelliferone 3, another natural coumarin.Incidentally this constituted its first synthesis.The formation of 3 was postulated to take place by domino Wittig reaction, Claisen rearrangement and two consecutive Cope rearrangements of the 2-prenyloxy group and intramolecular prenylation of the 4prenyloxy group.At this stage, we conjectured that if steric crowding in the molecule is increased the second Claisen rearrangement observed for the formation of 1 or the intramolecular prenylation observed in the formation of 3 may be precluded.If this happens we can synthesize balsamiferone 2, another natural coumarin from the same starting using appropriately substituted phosphorane.Towards this goal initially we condensed 5 with phosphorane 6a in refluxing diphenyl ether (Scheme 1).As speculated 3-allyl-7-hydroxy-6-prenyl coumarin 8 was obtained in 65% yield.Encouraged by this result we undertook synthesis of balsamiferone 2. Thus, 2,4diprenyloxybenzaldehyde 5 was heated with prenyl phosphorane 6b in a similar manner.We found that balsamiferone 2 was the only pure product obtained in 42% yield from the complex mixture.The spectral data of it were in accordance with literature data. 11The formation of 2 was rationalized by simultaneous Claisen-Cope rearrangements of the 2′-prenyloxy group of the intermediate ester (Scheme 2) to deliver the prenyl group at the 6-position of the coumarin nucleus and deprenylation of the 4′-prenyloxy group.

Scheme 2
Kapil et al. 12 have synthesized balsamiferone 2 beginning from umbelliferone-3-carboxylic acid in 13 steps.Cairns et al. 8c synthesized the target molecule 2 in six steps, via a cascade Claisen-Cope rearrangement, from 7-hydroxyumbelliferone via demethylsuberosin.Both the above examples use preformed coumarin as the starting material.Mali et al. 13 have reported one step synthesis of methyl ether of 2 using tandem Wittig and Claisen-Cope rearrangement from 2prenyloxy-4-methoxybenzaldehyde.However, these authors could not demethylate the methyl ether to 2 due to the problem of concurrent cyclisation to corresponding pyranocoumarin.The present synthesis of balsamiferone 2 described herein is the shortest route for this heterocycle.Similarly, further, when 5 was condensed with phosphorane 6c the corresponding 3-benzyl-7hydroxy-6-prenylcoumarin 9 was obtained in 20% yield while pyranocoumarin 10 was obtained in 40% yield.
Having tested the success in one pot deprenylation for the synthesis of 2 and direct intramolecular C-prenylation 10 for the synthesis of 3 we decided to study this protocol on 2,4-dio-(3,3-dimethylallyl)-5-methoxybenzaldehyde 14.If the 2′-prenyloxy group of the intermediate ester undergoes Claisen-Cope rearrangement, cyclisation and deprenylation then it would provide coumarin 17, since C-5 position is blocked (Scheme 3).Coumarin 17 is recently isolated 14 from Coriaria nephalensis.However, presence of the methoxy group at 5-position in 16 makes the benzene ring electron rich which should facilitate the intramolecular C-prenylation of one of the prenyloxy group rather than its sigmatropic rearrangement, leading to formation of cedrelopsin 4, a coumarin isolated from the bark of Cedrelopsis grevei. 7Thus, 2,4-di-(3,3dimethylallyl)-5-methoxybenzaldehyde 14 prepared from 2,4-dihydroxy-5-methoxy benzaldehyde 15 was heated with phosphorane 15 in diphenyl ether.The 1 H NMR data of the product obtained indicated that prenyl group is attached to the benzene ring rather than to the pyrone ring.The spectral data were in a close agreement with that of the natural product 4.The yield of this was found to be 45%.Cedrelopsin has been synthesized before by Anet et al. to confirm the structure of naturally occurring coumarin baryllin. 16The formation of 4 could be rationalized by deprenylation of one of the prenyloxy group and intramolecular C-prenylation of the other (Scheme 3).

Conclusions
In summary, a one step synthesis of naturally occurring coumarin balsamiferone 2 is achieved by domino Wittig reaction, Claisen-Cope rearrangement, deprenylation and lactonisation.The corresponding 3-allyl and 3-benzyl analogues were synthesized using the same protocol.Also a novel one pot synthesis of cedrelopsin 4, a natural prenylated coumarin, is accomplished using domino Wittig reaction, deprenylation, intramolecular prenylation and cyclisation.

Experimental Section
General.All reactions were carried out under an inert atmosphere.Solvents were purified & dried by standard procedure before use.Column chromatography was performed on silica gel (60-120mesh) and flash chromatography was performed on combi flash.Infrared Spectra (IR) were recorded in a Shimadzu FTIR instrument.NMR spectra were recorded on a Brucker 300MHz and 400MHz instruments using CDCl3 as solvent and TMS as internal standard.The multiplicities of carbon signal were obtained from DEPT experiments.HRMS were recorded on a micromass ES-QTOF.